Various approaches are known which describe the synthesis of substituted biphenyl imidazole compounds, which are useful in the synthesis of 1,2,4,5-substituted imidazoles, representing valuable intermediates in the synthesis of losartan.
Losartan potassium, being the first compound of a new class of drugs, was obtained, in a key step, via a heterogeneous Suzuki cross-coupling between trityltetrazole phenylboronic acid and 1-(4-bromobenzyl)-2-n-butyl-4-chloro-1H-imidazole-5-yl derivative (Larsen D. R., et al. J. Org. Chem. 1994, 59, 6391, U.S. Pat. No. 5,130,439, U.S. Pat. No. 5,310,928).
Larsen D. R., J. Org. Chem. 1994, 59, 6391 discloses a process of direct N-alkylation of 1H-imidazole derivatives to obtain a benzylated imidazole. This compound is reacted with a trityl-protected phenyltetrazole boronic acid via a Suzuki cross-coupling to give a losartan.
U.S. Pat. No. 5,310,928 discloses novel tetrazolylphenylboronic acids and their derivatives, methods for their preparation and their use in processes for the preparation of angiotensin II receptor antagonists via Suzuki cross-coupling reactions. Both Larson and U.S. Pat. No. 5,310,928 require the protection of the nitrogen atom at position 2 of the tetrazole moiety, since the unprotected tetrazole contaminates the catalyst [Smith, G. B.; Dezeny, G: C.; Hughes, D. L.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1994, 59, 8151.]. The protection of the tetrazole moiety is usually carried out by a trityl group [a) Larsen, R. D.; King, A. O.; Chen, C.; Y.; Corley, E. G.; Foster, B. S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Remwr, R. A.; Tschaen, D. M.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59, 6391. b) PCT Int. Appl., 9310106, 1993. c) Ger. Offen., 4313747, 1994.]. However, this methodology is not very effective, since the trityl group is quite labile and even traces of destrityl tetrazole boronic acid lower the yield of cross-coupling product significantly [Smith, G. B.; Dezeny, G: C.; Hughes, D. L.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1994, 59, 8151.].
A common method for the preparation of a tetrazole moiety is the transformation of a cyano group. Hird, M., J.C.S. Perkin. Trans. I. 1998, 20, 3479, Norman H. M., J. Med. Chem. 1995, 38, describe a Suzuki-Miyaura reaction wherein 2-bromobenzonitrile is used as an electrophile for the construction of 2-cyanobiphenyl. However, the problem of 2-cyanophenylboronic acid itself is its low stability, as it undergoes exothermic decomposition especially at temperatures over 90° C. [Urawa, Y.; Naka, H.; Miyazawa, M.; Souda, S.; Ogura, K. J. Organomet. Chem. 2002, 653, 269.]. Therefore, only few reports are available, describing the use of 2-cyanophenylboronic acid for cross-coupling reactions to give 2-cyanobiphenyl compounds in moderate yields (45-67%) [a) Thomas, A. P. et al., Bioorg. Med. Chem. Lett. 1994, 4, 2615; b) Yang, G. X. et al., Bioorg. Med. Chem. Lett. 2002, 12, 1497; c) Wu, T. Y. H. et al. Org. Lett. 2001, 3, 3827]. General methods for the preparation, properties and use of boronic acids and derivatives are summarized in “Metal-Organic Compounds”, Advances in Chemistry Series, No. 23, American Chemical Society, 1959).
In our own investigations, we found that the coupling of 2-cyanophenylboronic acid esters allows almost quantitative conversion of the 1-p-halobenzyl-1H-imidazole substrate to the coupling product, if the reaction conditions are adjusted accordingly. However, the corresponding boronates are only obtained in moderate yields, since their preparation from boronic acid requires heating and several crystallization steps to obtain the desired ester in a defined composition. This fact is of importance with regard to the considerable costs of o-cyanophenylboronic acid.
Recently, aryltrifluoroboronates have been reported as an alternative to arylboronic acids as substrates for the Suzuki cross-coupling reactions to obtain substituted biaryl compounds with aryl halides [a) Molander, G. A. et al., J. Org. Chem. 2003, 6E, 4302. b) Molander, G. A. et al., Org. Lett. 2002, 4, 1867]. However, it was unknown whether and to what extent a cyano substituent might interfere with this reaction. Since it is well known that hydrolysis of cyano groups results in the formation of the corresponding carboxylic acid, one would have expected at least the partial formation of undesired side products in aqueous media (Advanced Organic Chemistry, J. March, 4th Edition, page 888).
We have now surprisingly found that novel (2-cyanophenyl)-trifluoroboronates can be very efficiently prepared from o-cyanophenylboronic acid or acid derivatives. Such procedure allows using also 2-cyanophenylboronic acid of technical grade as a starting material. Such compounds are useful intermediates for the preparation of sartan derivatives.